The goal of this proposal is to develop and evaluate hyperpolarized helium-3 diffusion magnetic resonance imaging (He-3 dMRI) and low dose quantitative computed tomography (LD-QCT) indexes of emphysema as noninvasive biomarkers for the presence, severity, and progression of emphysema. Emphysema is a pathologic abnormality of the lungs defined by enlargement of terminal airspaces and destruction of airspace walls, and is commonly present in the millions of patients with chronic obstructive pulmonary disease. Increased knowledge regarding the role of inflammatory mechanisms and proteinases in the pathogenesis of COPD is leading to searches for newer anti-inflammatory strategies and enzyme inhibitors. Though in the early stages of development, some of these new approaches may eventually provide therapy that alters the course of the disease. Accurate biomarkers of emphysema would allow for early diagnosis, intervention, and evaluation of new therapies. Though spirometry is used to diagnose COPD, it is a relatively inaccurate means of assessing for emphysema. Conventional CT is a highly accurate way to assess the severity of emphysema, which can be quantified by the decrease in x-ray attenuation of the lungs that results from airspace enlargement and alveolar destruction. However, CT is performed using relatively high doses of ionizing radiation, which limits its acceptability as a screening and follow-up test, particularly in early or mild disease. In recent years, other noninvasive imaging tests for emphysema have been designed that require no or greatly reduced ionizing radiation. One new test, He-3 dMRI, uses a specially constructed MRI pulse sequence to measure the degree to which diffusivity of inhaled hyperpolarized He-3 gas is restricted by alveolar walls. This measurement, the apparent diffusion coefficient (ADC), is increased (gas diffusion is less restricted) when alveolar spaces are enlarged in emphysema. Another test, low dose CT scanning, allows depiction of substantial lung detail at less than 20 percent of the radiation dose of conventional CT, but has not been developed for quantitation of emphysema. Though promising, the optimal technique and validity of both He-3 dMRI and LD-QCT have yet to be established. We hypothesize that 1) Optimizing He-3 dMRI and LD-QCT techniques will allow sensitive and accurate assessment of emphysema, compared to lung morphometry, 2) The optimized He-3 dMRI and LD-QCT techniques will provide valid biomarkers of emphysema that can be applied to other populations, and 3) He-3 dMRI and LD-QCT will allow identification of emphysema progression over time. We will study three separate groups of subjects. In the first group, we will determine which scanning and analysis parameters provide ADC and LD-QCT biomarkers that most accurately quantify the amount of emphysema present pathologically in lobectomy specimens (Aim I). We will then use the optimized scanning and analysis techniques to validate these measurements in a different group, compared to the amount of emphysema present in lobectomy specimens (Aim II). In a third group of subjects, we will determine ADC and LD-QCT lung attenuation measurements at serial time points to assess for emphysema progression (Aim III).